Serotonin therapies for opioid-induced disordered swallow and respiratory depression.

Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We tested the effects of the clinically relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated the utility of 5-HT1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague-Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus, and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing. We evaluated the hypotheses that swallowing varies by stimulus, opioids depress swallowing and breathing, and that 5-HT1A agonists improve these depressions. Our results largely confirmed the following hypotheses: 1) swallow-related EMG activity was larger during swallows elicited by esophageal distension plus oral water infusion than by either stimulus alone. 2) Buprenorphine depressed swallow in both sexes, but females were more susceptible to total swallow suppression. 3) Female animals were also more vulnerable to opioid-induced respiratory depression. 4) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pretreatment with the partial 5-HT1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5) 8-OH-DPAT enhanced mylohyoid and thyropharyngeus EMG amplitude during swallow but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide preclinical evidence of a 5HT1A agonist for the treatment of respiratory depression and dysphagia.NEW & NOTEWORTHY This is the first study, to our knowledge, to evaluate sex-specific effects of opioid administration on pharyngeal swallow. We expand on a small but growing number of studies that report a lower threshold for opioid-induced respiratory depression in females compared with males, and we are the first to produce this effect with the partial µ-opioid-receptor agonist buprenorphine. This is the first demonstration, to our knowledge, that activation of 5-HT1A receptors can improve swallow and breathing outcomes following systemic buprenorphine administration.

Buspirone for the treatment of anxiety in Williams syndrome: a retrospective chart review study.

BACKGROUND: Williams syndrome (WS) is a rare genetic disorder associated with a high prevalence of anxiety disorders. Evidence-based pharmacologic treatments for anxiety in WS are lacking. The purpose of this study is to provide naturalistic data on the use of buspirone for the treatment of anxiety in WS. RESEARCH DESIGN AND METHODS: Medical records of 24 individuals with Williams syndrome (ages 7-47 years) and anxiety who received treatment with buspirone were reviewed. Treatment response to buspirone was rated by assigning a retrospective Clinical Global Impression Improvement subscale (CGI-I) score. RESULTS: Twenty-three of 24 (96%) patients completed at least a 16-week treatment course with buspirone. Sixteen patients (67%; 95% CI 47%, 82%) were treatment responders (CGI-I ≤ 2). Only 1 (4%) patient discontinued buspirone due to a treatment-emergent side effect (nausea and vomiting). The most common side effect was nausea (13%). Twenty (84%) patients remained on buspirone at the time of their most recent follow-up visit. CONCLUSIONS: In this retrospective study, the majority of patients responded to a 16-week course of buspirone. Prospective studies are warranted to further assess the efficacy and tolerability of buspirone for anxiety in WS.

Buspirone Ameliorates Colon Inflammation in TNBS-Induced Rat Acute Colitis: The Involvement of TLR4/NF-kB Pathway.

Inflammatory bowel disease (IBD) is an inflammatory situation involving the whole digestive system. This illness includes ulcerative colitis and Crohn's disease. According to scientific research, the immune system plays an essential part in developing this disease. Recently, buspirone has been discovered to have anti-inflammatory properties. As a result, this research aims to see if buspirone provides anti-inflammatory effects in a rat model of TNBS-induced colitis. Control, TNBS, dexamethasone (2 mg/kg), and buspirone (5, 10, and 20 mg/kg) were randomly given to six groups of 36 male Wistar rats. Colitis was induced by intrarectal instillation of TNBS in all research groups except the control group, and rats were meliorated with dexamethasone and buspirone. Macroscopic and microscopic lesions appeared after colitis induction, while therapy with dexamethasone and buspirone significantly improved the lesions. TLR4 and pNF-κB expression were also enhanced during colitis induction. On the other hand, the administration of dexamethasone or buspirone resulted in a considerable reduction in their expression. Tissue TNF-α and MPO activity were enhanced after induction of colitis in terms of biochemical variables; however, administration of dexamethasone or buspirone reduced TNF-α and MPO activity. Eventually, in an animal model of severe colitis, buspirone displayed anti-inflammatory characteristics via lowering the TLR4/NF-ĸB signaling pathway's activity in an animal model of acute colitis.

Pregnancy outcomes after first-trimester exposure to buspirone: prospective longitudinal outcomes from the MGH National Pregnancy Registry for Psychiatric Medications.

Buspirone is commonly used to treat anxiety disorders among reproductive-aged women. To date, the reproductive safety of buspirone in humans has been particularly sparse. We sought to provide preliminary data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications (NPRPM) on the risk of major malformations after first-trimester buspirone exposure. The NPRPM enrolls pregnant women with psychiatric disorders to prospectively assess for major congenital malformations after in utero exposure to psychotropics. Women are interviewed twice during pregnancy and once at 12 weeks postpartum. Data regarding women who took buspirone during the first trimester were extracted from the NPRPM database. Data were assessed as a rigorously ascertained case series to determine the incidence of major malformations among those exposed to buspirone. The primary outcome was obtained by maternal postpartum interview and medical record review. As of January 6, 2022, N = 97 women enrolled in the registry took buspirone during their first trimester. Of these women, 68 were evaluable and eligible for this analysis. Four women had twins, resulting in 72 infants. Among this sample, there were no malformations present. These preliminary data represent the only prospectively ascertained sample of pregnancy outcomes after first-trimester buspirone exposure. Albeit a small sample, no major malformations were observed in this cohort. The rigorous prospective ascertainment of outcomes is a strength of this study. Future analyses are planned that will include larger numbers of women with exposures to buspirone and comparison with control groups matched for demographic and diagnostic variables.

Buspirone-associated Movement Disorder: A Literature Review.

Buspirone (BUS) belongs to the azapirone chemical class. The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of BUS-associated movement disorders (MD). Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 25 reports containing 65 cases were assessed. The MD associated with BUS were: dyskinesia in 14 cases, 10 of akathisia, 8 of myoclonus, 6 of Parkinsonism, and 6 of dystonia. The cases not clearly defined were 7 tension, 14 incoordination, and the undefined number of dyskinesia, tics, and Parkinsonism. The mean age was 45.23 years (range: 15-74). The male was the predominant sex in 60.86% and the most common BUS-indication was anxiety disorder. The mean BUS-dose was 42.16 mg (range: 5-100). The time from the beginning of BUS administration to the MD onset was one month or less in 76%. The time from BUS withdrawal to complete recovery was within one month in 87.5%. The most common management was BUS withdrawal. In 16 patients the follow-up was reported: 14 had a full recovery, but in two (1 dyskinesia + 1 dystonia) the symptoms continued after the BUS withdrawal. MD associated with BUS were scarcely reported in the literature. Moreover, in the majority of cases, no clear description of the clinical profile, neurological examination, or the time data of the movement disorder onset and recovery were given.

Pharmacotherapies for cannabis dependence.

BACKGROUND: Globally, cannabis use is prevalent and widespread. There are currently no pharmacotherapies approved for treatment of cannabis use disorders.This is an update of a Cochrane Review first published in the Cochrane Library in Issue 12, 2014. OBJECTIVES: To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or no pharmacotherapy (supportive care) for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use. SEARCH METHODS: We updated our searches of the following databases to March 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and Web of Science. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs involving the use of medications to treat cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in people diagnosed as cannabis dependent or who were likely to be dependent. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 21 RCTs involving 1755 participants: 18 studies recruited adults (mean age 22 to 41 years); three studies targeted young people (mean age 20 years). Most (75%) participants were male. The studies were at low risk of performance, detection and selective outcome reporting bias. One study was at risk of selection bias, and three studies were at risk of attrition bias.All studies involved comparison of active medication and placebo. The medications were diverse, as were the outcomes reported, which limited the extent of analysis.Abstinence at end of treatment was no more likely with Δ9-tetrahydrocannabinol (THC) preparations than with placebo (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.64 to 1.52; 305 participants; 3 studies; moderate-quality evidence). For selective serotonin reuptake inhibitor (SSRI) antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine, there was no difference in the likelihood of abstinence at end of treatment compared to placebo (low- to very low-quality evidence).There was qualitative evidence of reduced intensity of withdrawal symptoms with THC preparations compared to placebo. For other pharmacotherapies, this outcome was either not examined, or no significant differences was reported.Adverse effects were no more likely with THC preparations (RR 1.02, 95% CI 0.89 to 1.17; 318 participants; 3 studies) or N-acetylcysteine (RR 0.94, 95% CI 0.71 to 1.23; 418 participants; 2 studies) compared to placebo (moderate-quality evidence). For SSRI antidepressants, mixed action antidepressants, buspirone and N-acetylcysteine, there was no difference in adverse effects compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of withdrawal from treatment due to adverse effects with THC preparations, SSRIs antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine compared to placebo (low- to very low-quality evidence).There was no difference in the likelihood of treatment completion with THC preparations, SSRI antidepressants, mixed action antidepressants and buspirone compared to placebo (low- to very low-quality evidence) or with N-acetylcysteine compared to placebo (RR 1.06, 95% CI 0.93 to 1.21; 418 participants; 2 studies; moderate-quality evidence). Anticonvulsants and mood stabilisers appeared to reduce the likelihood of treatment completion (RR 0.66, 95% CI 0.47 to 0.92; 141 participants; 3 studies; low-quality evidence).Available evidence on gabapentin (anticonvulsant), oxytocin (neuropeptide) and atomoxetine was insufficient for estimates of effectiveness. AUTHORS' CONCLUSIONS: There is incomplete evidence for all of the pharmacotherapies investigated, and for many outcomes the quality of the evidence was low or very low. Findings indicate that SSRI antidepressants, mixed action antidepressants, bupropion, buspirone and atomoxetine are probably of little value in the treatment of cannabis dependence. Given the limited evidence of efficacy, THC preparations should be considered still experimental, with some positive effects on withdrawal symptoms and craving. The evidence base for the anticonvulsant gabapentin, oxytocin, and N-acetylcysteine is weak, but these medications are also worth further investigation.

Pupillary capture of implantable collamer lens after oral antidepressants.

We report the case of a 26-year-old man under treatment with the antidepressant drugs olanzapine and buspirone, which are associated with anticholinergic effects, in whom an implantable collamer lens (ICL) became spontaneously dislocated. ICL dislocation and pupil capture occurred 10 months postoperatively. The lens was successfully repositioned. The possible role of these drugs in the dislocation of the ICL is discussed.

Psychotropic Pharmacotherapy Associated With QT Prolongation Among Veterans With Posttraumatic Stress Disorder.

BACKGROUND: In 2012, the Food and Drug Administration issued Drug Safety Communications on several drugs associated with QT prolongation and fatal ventricular arrhythmias. Among these was citalopram, a selective serotonin reuptake inhibitor (SSRI) approved for depression and commonly used for posttraumatic stress disorder (PTSD). Evaluation of the risk for QT prolongation among other psychotropic drugs for individuals with PTSD remains limited. OBJECTIVE: Explore psychotropic drugs associated with QT prolongation among veterans with PTSD. METHODS: Patients in the Veterans Health Administration in 2006-2009 with PTSD and QT prolongation (176 cases) were matched 1:4 on age, gender, visit date and setting, and physical comorbidity. Classification trees assessed QT prolongation risk among prescribed medications (n=880). RESULTS: Receipt of any drug with known risk of QT prolongation varied by group (23% QT cases vs 15% control, p<0.01). Psychotropic medications conferring significant risks included ziprasidone (3% vs 1%, p=0.02) and buspirone (6% vs 2%, p=0.01). Increased risk was not observed for the SSRIs, citalopram and fluoxetine. Classification trees found that sotalol and amitriptyline carried greater risk among cardiac patients and methadone, especially if prescribed with quetiapine, among noncardiac patients. Per adjusted survival model, patients with QT prolongation were at increased risk for death (hazard ratio=1.60; 95% CI=1.04-2.44). CONCLUSIONS: Decision models are particularly advantageous when exploring nonlinear relationships or nonadditive interactions. These findings may potentially affect clinical decision-making concerning treatment for PTSD. For patients at higher risk of QT prolongation, antidepressants other than amitriptyline should be considered. Medications for comorbid conditions should also be closely monitored for heightened QT prolongation risk.

Buspirone in Children and Adolescents with Anxiety: A Review and Bayesian Analysis of Abandoned Randomized Controlled Trials.

OBJECTIVES: An increasing number of abandoned clinical trials have forestalled efforts to advance the evidence base for the treatment of mood and anxiety disorders in children and adolescents. With this in mind, we sought to present and validate a Bayesian approach for the reanalysis of summary data in abandoned clinical trials and to review and re-evaluate available pharmacokinetic, tolerability, and efficacy data from two large, randomized controlled trials of buspirone in pediatric patients with generalized anxiety disorder (GAD). METHODS: Prospective, randomized, parallel-group controlled trials of buspirone in pediatric patients with GAD as well as associated pharmacokinetic studies were identified and data were extracted. In addition to descriptive statistics, marginal posterior densities for each variable of interest were determined and a Monte Carlo pseudosample was generated with random draws obtained from the Student's t-distribution to assess, with inferential statistics, differences in variables of interest. RESULTS: Buspirone was evaluated in one flexibly dosed (N = 227) and one fixed-dose (N = 341) trial in children and adolescents aged 6-17 years with a primary diagnosis of GAD. With regard to improvement in the sum of the Columbia Schedule for Affective Disorders and Schizophrenia GAD items, buspirone did not separate from placebo in the fixed-dose trial at low (95% CI: -0.78 to 2.39, p = 0.32) or high dose (95% CI: -0.87 to 1.87, p = 0.47) nor did it separate from placebo in the flexibly dosed study (95% CI: -0.3 to 1.9, p = 0.15). Drop out as a result of a treatment-emergent adverse event was significantly greater in buspirone-treated patients compared to placebo (p = 0.011). Side effects were consistent with the known profile of buspirone with lightheadedness occurring more frequently in buspirone-treated patients (p < 0.001). CONCLUSIONS: Buspirone is well tolerated in pediatric patients with GAD, although two randomized controlled trials were underpowered to detect small effect sizes (Cohen's d < 0.15). Finally, Bayesian approaches may facilitate re-examination of data from abandoned clinical trials.

Adjunctive azapirone for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials.

Azapirones, which are serotonin1A (5-HT1A) receptor partial agonists, have been used as an adjunctive treatment for schizophrenia with mixed results. This is a meta-analysis of the efficacy and tolerability of azapirones for schizophrenia based on randomized, double-blind, placebo-controlled trials (RCTs). English and Chinese databases were systematically and independently searched by two investigators. Data were extracted and analyzed using the RevMan software (version 5.3). Seven RCTs (n = 368) of azapirones (buspirone in 6 RCTs and tandospirone in 1 RCT) were identified and analyzed. Only adjunctive buspirone outperformed placebo regarding total psychopathology [standardized mean difference: -1.03 (95% confidence interval (CI): -1.91, -0.15), P = 0.02; I2 = 92%], but the significance disappeared in sensitivity analysis after removing two outlying studies, and in 10 of the 12 subgroup analyses. In 5 RCTs examining neurocognitive function of azapirones, only 2 RCTs found the superiority of buspirone in improving attention/speeded motor performance, verbal and performance intelligence. Adjunctive buspirone outperformed placebo regarding extrapyramidal symptoms [SMD:-0.51, (95%CI: -0.99, -0.02), P = 0.04; I2 = 0%]. Similar rates of discontinuation [risk ratio:1.06 (95%CI:0.54, 2.07), P = 0.86, I2 = 0%] and adverse drug reactions were found between both groups. Adjunctive buspirone and tandospirone failed to show efficacy for psychotic symptoms, but adjunctive buspirone may be associated with improvement in extrapyramidal symptoms and cognitive deficits in schizophrenia. Due to the preliminary nature of this meta-analysis, larger sample size and higher quality RCTs are needed to confirm these finding.

Beyond anxiety and agitation: A clinical approach to akathisia.

BACKGROUND: When patients suddenly become restless and are unable to sit or stand still, especially in general medical settings, anxiety is often the topmost differential on every clinician's mind. However, the possibility of the very subjectively distressing condition called 'akathisia' should always be considered. OBJECTIVE: The aim of this article is to discuss a clinical approach to the management of akathisia, drawing on the presentation of a patient who was admitted to a general medical ward. DISCUSSION: Akathisia, a subjective and very distressing feeling of restlessness, has been found to be caused by a wide range of medications used in general medical settings, such as azithromycin, antiemetics and antipsychotics. Despite its high incidence and association with an increase in suicidal thoughts, it often goes unrecognised. This paper highlights the need for its early recognition, provides a diagnostic guide and an approach to its management.

Buspirone reduces sexual risk-taking intent but not cocaine self-administration.

Impulsive sexual decision-making may underlie sexual risk-taking behavior that contributes to the disproportionately high prevalence of HIV infection among cocaine users. Delay-discounting procedures measure impulsive decision-making and may provide insight into the underlying mechanisms of sexual risk-taking behavior. The anxiolytic drug buspirone reduces delay discounting in rats and blunts the reinforcing effects of cocaine in some preclinical studies suggesting that it might have utility in the treatment of cocaine-use disorders. This study determined whether buspirone mitigates impulsive risky sexual decision-making in cocaine users on a sexual delay-discounting procedure. The effects of buspirone maintenance on the abuse-related and physiological effects of cocaine were also tested. Nine (N = 9) current cocaine users completed a repeated-measures, inpatient protocol in which sexual delay discounting was assessed after 3 days of maintenance on placebo and buspirone (30 mg/day) in counterbalanced order. The reinforcing, subject-rated, and physiological effects of placebo and intranasal cocaine (15 and 45 mg) were also assessed during buspirone and placebo maintenance. Buspirone increased the likelihood of condom use for hypothetical sexual partners that were categorized as most likely to have a sexually transmitted infection and least sexually desirable. Cocaine functioned as a reinforcer and increased positive subjective effects ratings, but buspirone maintenance did not impact these effects of cocaine. Buspirone was also safe and tolerable when combined with cocaine and may have blunted some its cardiovascular effects. The results from the sexual delay-discounting procedure indicate that buspirone may reduce preference for riskier sex in cocaine users. (PsycINFO Database Record

Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans.

There is considerable interest in blocking the dopamine D3 receptor (DRD3) versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.

Buspirone treatment of cannabis dependence: A randomized, placebo-controlled trial.

BACKGROUND: The purpose of this study was to evaluate the efficacy of buspirone, a partial 5-HT1A agonist, for treatment of cannabis dependence. METHODS: One hundred seventy-five cannabis-dependent adults were randomized to receive either up to 60mg/day of buspirone (n=88) or placebo (n=87) for 12 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests. RESULTS: Participants in both groups reported reduced cannabis craving over the course of the study; however, buspirone provided no advantage over placebo in reducing cannabis use. Significant gender by treatment interactions were observed, with women randomized to buspirone having fewer negative urine cannabinoid tests than women randomized to placebo (p=0.007), and men randomized to buspirone having significantly lower creatinine adjusted cannabinoid levels as compared to those randomized to placebo (p=0.023). An evaluation of serotonin allelic variations did not find an association with buspirone treatment response. CONCLUSIONS: Buspirone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes with buspirone treatment. Considerations for future medication trials in this challenging population are discussed.

[The current concept of augmentation of treatment efficiency with antidepressant medication].

The introduction into clinical practice of new and highly effective antidepressants has certainly helped to resolve the problem of depression therapy. However, achieving a complete remission, which is a key point for therapy in depressed patients, remains a difficult task. It is known that a significant number of patients do not respond to antidepressants. So, special attention has been paid in recent years towards investigation of methods that could improve the treatment effectiveness in depressive. In this review presents the results of clinical trials of buspirone as an adjunctive therapy in cases with previous ineffective use of antidepressants in patients with major depressive disorder.